# SMARCA4-Deficient Carcinomas of the Small Intestine: A Systematic Review

## TL;DR

This paper reviews rare, aggressive small intestine cancers caused by loss of the SMARCA4 gene, highlighting their poor prognosis and the need for early detection and specialized treatment.

## Contribution

The study systematically reviews SMARCA4-deficient carcinomas of the small intestine, a rare and understudied cancer subtype.

## Key findings

- Most patients were middle-aged men with advanced disease and nonspecific symptoms.
- Tumors showed aggressive features and poor survival, with limited response to immune checkpoint inhibitors.
- Early diagnosis and SMARCA4 testing are critical for guiding treatment and referral to specialized centers.

## Abstract

Cancers of the small intestine are rare, and some aggressive forms are difficult to diagnose and treat. One such form involves loss of a gene called SMAR-CA4, which normally helps control how cells grow and divide. When this gene is lost, cancers tend to grow quickly and respond poorly to standard treatments. Most knowledge about SMARCA4-deficient cancers comes from tumors in the chest and very little is known about those arising in the small intestine. In this study, we reviewed all published cases of SMARCA4-deficient small intestine cancer to better understand how these tumors present, how they look under the microscope, how they behave and how patients respond to treatment. We found that most patients were middle-aged men who presented with advanced disease and vague symptoms such as abdominal pain or bowel obstruction. These cancers showed highly aggressive features and were associated with short survival in most cases. Surgery combined with chemotherapy offered longer survival only in patients diagnosed early. Recognizing this rare cancer early and testing for SMARCA4 loss is critical, as it may guide treatment decisions and referral to specialized centers.

Purpose: SMARCA4-deficient carcinomas are rare, aggressive malignancies characterized by loss of BRG1, a core component of the SWI/SNF chromatin remodeling complex. These typically arise in the chest, but recent case reports suggest rare involvement of the gastrointestinal tract, particularly the small intestine. This review aims to consolidate the available literature on SMARCA4-deficient carcinomas of the small intestine, highlighting their clinical, histopathological, molecular, and therapeutic features. Design: A systematic review of PubMed was conducted through March 2025 to identify all published cases of primary SMARCA4-deficient carcinomas of the small intestine. Inclusion criteria required immunohistochemical or molecular confirmation of SMARCA4/BRG1 loss. Studies describing metastases, non-small intestine primaries, or lacking molecular data were excluded. Ten eligible cases were analyzed in detail. Results: Patients were predominantly male (9 out of 10) with a median age of 54 years. Most carcinomas arose in the duodenum and patients frequently presented with nonspecific symptoms and advanced-stage disease. Histologically, tumors demonstrated undifferentiated or rhabdoid features with high mitotic activity and extensive necrosis. Immunohistochemistry confirmed loss of SMARCA4, while several cases also showed SMARCA2 loss. Molecular profiling revealed congruent mutations in TP53 and CTNNB1, among oncogenic drivers. While some patients with localized disease achieved prolonged survival after surgery and adjuvant chemotherapy, those with metastatic disease had limited responses to immune checkpoint inhibitors, despite PD-L1 positivity in a subset. Overall survival ranged from 2 to 29 months. Conclusions: SMARCA4-deficient carcinomas of the small intestine represent a distinct, high-grade malignancy with poor prognosis and limited therapeutic options. Prompt recognition, SMARCA4 testing, and referral to specialized centers are essential. Prospective studies are needed to guide therapy and explore targeted approaches in this challenging carcinoma subtype.